Numerous nuclear receptors including farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptors, pregnane X receptor, hepatic nuclear factors have been extensively studied within the context of non-alcoholic fatty liver disease (NAFLD). Following the first description of the Aryl hydrocarbon Receptor (AhR) in the 1970s and decades of research which unveiled its role in toxicity and pathophysiological processes, the functional significance of AhR in NAFLD has not been completely decoded. Recently, multiple research groups have utilized a plethora of in vitro and in vivo models that mimic NAFLD pathology to investigate the functional significance of AhR in fatty liver disease. This review provides a comprehensive account of studies describing both the beneficial and possible detrimental role of AhR in NAFLD. A plausible reconciliation for the paradox indicating AhR as a ‘double-edged sword’ in NAFLD is discussed. Finally, understanding AhR ligands and their signaling in NAFLD will facilitate us to probe AhR as a potential drug target to design innovative therapeutics against NAFLD in the near future.

We recently identified upregulation of a novel aryl hydrocarbon receptor (AhR) target gene, stanniocalcin 2 (STC2), by an endogenous AhR agonist, cinnabarinic acid (CA). STC2 is a disulfide-linked homodimeric secreted glycoprotein that plays a role in various physiologic processes, including cell metabolism, inflammation, endoplasmic reticulum (ER) and oxidative stress, calcium regulation, cell proliferation, and apoptosis. Our previous studies have confirmed that CA-induced AhR-dependent STC2 expression was able to confer cytoprotection both in vitro and in vivo in response to injury induced by variety of ER/oxidative insults. Here, we used mouse models of chronic and acute ethanol feeding and demonstrated that upregulation of STC2 by CA was critical for cytoprotection. In STC2 knockout mice (STC2^−/−), CA failed to protect against both acute as well as chronic-plus-binge ethanol-induced liver injury, whereas re-expression of STC2 in the liver using in vivo gene delivery restored cytoprotection against injury based on measures of apoptosis and serum levels of liver enzymes, underlining STC2’s indispensable function in cell survival. In conclusion, the identification of STC2 as an AhR target gene receptive to CA-mediated endogenous AhR signaling and STC2’s role in providing cytoprotection against liver injury represents a key finding with potentially significant therapeutic implications. SIGNIFICANCE STATEMENT We recently identified stanniocalcin 2 (STC2) as a novel aryl hydrocarbon receptor (AhR) target gene regulated by endogenous AhR agonist and tryptophan metabolite, cinnabarinic acid (CA). Here, we showed that CA-induced STC2 expression conferred cytoprotection against apoptosis, steatosis, and liver injury in chronic as well as acute models of ethanol feeding. Therefore, this study will prove instrumental in developing CA as a promising lead compound for future drug development against hepatic diseases.

We have previously shown that a bona fide Aryl hydrocarbon Receptor (AhR) agonist, cinnabarinic acid (CA) protect against alcohol-induced hepatocyte apoptosis via activation of a novel AhR target gene, stanniocalcin 2 (Stc2). Stc2 translates to a secreted disulfide-linked hormone, STC2 known to function in cell development, calcium and phosphate regulation, angiogenesis, and anti-apoptosis - albeit the comprehensive mechanism by which CA-AhR-STC2 axis confers anti-apoptosis is yet to be characterized. In this study, using RNA interference library screening, downstream anti-apoptotic molecular signaling components involved in CA-induced STC2-mediated protection against ethanol-induced apoptosis were investigated. RNA interference library screening of kinases and phosphatases in Hepa1 cells, and subsequent pathway analysis identified mitogen-activated protein kinase (MAPK) signaling as a critical molecular pathway involved in CA-mediated protection. Specifically, phosphorylation of ERK1/2 was induced in response to CA treatment without alterations in p38 and JNK signaling pathways. Silencing Stc2 in Hepa1 cells and in vivo experiments performed in Stc2^-/- (Stc2 knockout) mice - which failed to confer CA-mediated protection against ethanol-induced apoptosis - showed abrogation of ERK1/2 activation, underlining significance of ERK1/2 signaling in CA-STC2 mediated protection. In conclusion, activation of ERK1/2 signaling in CA-driven AhR-dependent Stc2-mediated protection represents a novel mechanism of protection against acute alcohol-induced apoptosis. Significance Statement We have previously shown role of stanniocalcin 2 (Stc2) in CA-mediated protection against alcohol-induced apoptosis. Here, using RNA interference library screening and subsequent in vivo studies, functional significance of ERK1/2 activation in CA-induced Stc2-mediated protection against acute ethanol-induced apoptosis was identified. This study is thus significant as it illustrates a comprehensive downstream mechanism by which CA-induced Stc2 protects against alcoholic liver disease.